Inefficient cleavage of palmitoyl-protein thioesterase (PPT) substrates by aminothiols: Implications for treatment of infantile neuronal ceroid lipofuscinosis

详细信息    查看全文

• 作者：J.-Y. Lu and S. L. Hofmann
• 刊名：Journal of Inherited Metabolic Disease
• 出版年：2006
• 出版时间：February 2006
• 年：2006
• 卷：29
• 期：1
• 页码：119-126
• 全文大小：319 KB

文摘

Infantile neuronal ceroid lipofuscinosis (INCL, also known as infantile Batten disease) is a devastating neurodegenerative disorder caused by deficiency in the lysosomal enzyme palmitoyl-protein thioesterase (PPT, or CLN1), which functions to remove long-chain fatty acids from cysteine residues in proteins. A previous study suggested that the drug cysteamine, a simple aminothiol used in the treatment of cystinosis, may have utility in the treatment of INCL. In the current study, we compared the catalytic rate constants for the conversion of palmitoyl-CoA (a PPT substrate) and cystine (which accumulates in cystinosis) by cysteamine. We found that while cysteamine can react with palmitoyl-CoA, the rate constant is 103-fold less than the reaction with cystine. StructureR11;activity studies suggested that it is the thiolate ion that is reactive in the cleavage reaction and that the amino group probably facilitates lysosomal entry. A modest effect of cysteamine (and two related aminothiols, WR 1065 and dimethylaminoethanethiol, DMAET) on PPT substrate accumulation in INCL lymphoblasts was observed. However, at optimum concentration a paradoxical increase in saposin immunoreactivity was seen, indicating possible lysosomal dysfunction. Improvements are needed in the design of small molecules for the treatment of INCL disease.